Methods of improving cell-based therapy

Abstract

Provided are methods for improving the efficacy and success of cell-based therapies by administration of stem cells which have been preconditioned with an inhibitor of soluble epoxide hydrolase (sEHI), as well as kits, stents and patches for administering sEHI-preconditioned stem cells, as sole active agent or in combination with an agent that increases the production and or levels of EETs.

What is claimed is: 
     
       1. A method of increasing, improving and/or promoting the survival, engraftment, and/or integration of transplanted stem cells in a tissue of a subject in need thereof, comprising:
 a) exposing a population stem cells in vitro to an agent that increases the production and/or level of epoxy fatty acids (EpFA), or mimics thereof, under conditions and for a time sufficient to increase epoxy fatty acids (EpFA) and/or inhibit soluble epoxide hydrolase in the stem cells, thereby producing preconditioned stem cells; and 
 b) administering to the subject the preconditioned stem cells, wherein the stem cells are selected from multipotent stem cells, pluripotent stem cells, and induced pluripotent stem cells. 
 
     
     
       2. The method of  claim 1 , wherein the stem cells are exposed in vitro to the agent at a concentration between about 0.1 nM to about 20 μM. 
     
     
       3. The method of  claim 1 , wherein the stem cells are exposed in vitro to the agent for a time period between about 0.5 days to about 10 days. 
     
     
       4. The method of  claim 1 , further wherein the preconditioned stem cells are co-administered to the subject with an agent that increases the production and/or level of epoxy fatty acids (EpFA), or mimics thereof. 
     
     
       5. The method of  claim 1 , wherein the subject has cardiomyopathy or heart failure. 
     
     
       6. The method of  claim 5 , wherein the cardiomyopathy is one or more of hypertrophic cardiomyopathy, hypertensive cardiomyopathy, diabetic cardiomyopathy, ischemic cardiomyopathy, restrictive cardiomyopathy and dilated cardiomyopathy. 
     
     
       7. The method of  claim 5 , wherein said cardiomyopathy is due to or secondary to one or more of valvular heart disease, myocardial infarction, ischemic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (ARVC) or familial hypertrophic cardiomyopathy. 
     
     
       8. The method of  claim 5 , wherein the cardiomyopathy is dilated cardiomyopathy. 
     
     
       9. The method of  claim 8 , wherein said dilated cardiomyopathy is one or more of alcohol-induced cardiomyopathy, drug-induced cardiomyopathy, viral-induced cardiomyopathy, familial dilated cardiomyopathy and dilated cardiomyopathy is caused by administration of an anti-cancer drug or exposure to a toxic agent. 
     
     
       10. The method of  claim 1 , wherein the administration of said stem cells and said agent or agents inhibits cardiac arrhythmia. 
     
     
       11. The method of  claim 1 , wherein the agent that increases the production and/or level of epoxy fatty acids (EpFA) is an inhibitor of soluble epoxide hydrolase (“sEH”). 
     
     
       12. The method of  claim 11 , wherein the inhibitor of sEH is selected from the group consisting of:
 a) 3-(4-chlorophenyl)-1-(3,4-dichlorphenyl)urea or 3,4,4′-trichlorocarbanilide (TCC; compound 295); 
 b) 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA; compound 700); 
 c) 1-adamantanyl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl]}urea (AEPU; compound 950); 
 d) 1-(1-acetypiperidin-4-yl)-3-adamantanylurea (APAU; compound 1153); 
 e) trans-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB; compound 1471); 
 f) cis-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (cAUCB; compound 1686); 
 g) 1-(1-methylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPS; compound 1709); 
 h) trans-4-{4-[3-(4-Trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzoic acid (tTUCB; compound 1728); 
 i) 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU; compound 1770); 
 j) 1-(1-ethylsulfonyl-piperidin-4-yl)-3-(4-trifluoromethoxy-phenyl)-urea (TUPSE; compound 2213); 
 k) 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (CPTU; compound 2214); 
 l) trans-N-methyl-4-[4-(3-Adamantan-1-yl-ureido)-cyclohexyloxy]-benzamide (tMAUCB; compound 2225); 
 m) trans-N-methyl-4-[4-((3-trifluoromethyl-4-chlorophenyl)-ureido)-cyclohexyloxy]-benzamide (tMTCUCB; compound 2226); 
 n) cis-N-methyl-4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy}-benzamide (cMTUCB; compound 2228); 
 o) 1-cycloheptyl-3-(3-(1,5-diphenyl-1H-pyrazol-3-yl)propyl)urea (HDP 3 U; compound 2247); 
 p) trans-2-(4-(4-(3-(4-trifluoromethoxy-phenyl)-ureido)-cyclohexyloxy)-benzamido)-acetic acid (compound 2283); 
 q) N-(methylsulfonyl)-4-(trans-4-(3-(4-trifluoromethoxy-phenyl)-ureido)-cyclohexyloxy)-benzamide (compound 2728); 
 r) 1-(trans-4-(4-(1H-tetrazol-5-yl)-phenoxy)-cyclohexyl)-3-(4-(trifluoromethoxy)-phenyl)-urea (compound 2806); 
 s) 4-(trans-4-(3-(2-fluorophenyl)-ureido)-cyclohexyloxy)-benzoic acid (compound 2736); 
 t) 4-(4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-phenoxy)-benzoic acid (compound 2803); 
 u) 4-(3-fluoro-4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-phenoxy)-benzoic acid (compound 2807); 
 v) N-hydroxy-4-(trans-4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-cyclohexyloxy)-benzamide (compound 2761); 
 w) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-((1r,4r)-4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-cyclohexyloxy)-benzoate (compound 2796); 
 x) 1-(4-oxocyclohexyl)-3-(4-(trifluoromethoxy)-phenyl)-urea (compound 2809); 
 y) methyl 4-(4-(3-(4-(trifluoromethoxy)-phenyl)-ureido)-cyclohexylamino)-benzoate (compound 2804); 
 z) 1-(4-(pyrimidin-2-yloxy)-cyclohexyl)-3-(4-(trifluoromethoxy)-phenyl)-urea (compound 2810); 
 aa) 4-(trans-4-(3-(4-(difluoromethoxy)-phenyl)-ureido)-cyclohexyloxy)-benzoic acid (compound 2805); 
 bb) (1R,3S)—N-(4-cyano-2-(trifluoromethyl)benzyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexane-1-carboxamide (GSK2256294A); 
 cc) sorafenib (4-(4-(3-(4-chloro-3-4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide); 
 dd) regorafenib (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide); 
 ee) triclocarban (3-(4-chlorophenyl)-1-(3,4-dichlorphenyl)urea or 3,4,4′-trichlorocarbanilide); 
 
       and mixtures thereof. 
     
     
       13. The method of  claim 11 , wherein the inhibitor of sEH is selected from the group consisting of 1-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(1-(tetrahydro-2H-pyran-4-carbo-nyl)piperidin-4-yl)urea (Compound 29 of Table 3) and 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU). 
     
     
       14. The method of  claim 1 , wherein the agent that increases the production and/or level of epoxy fatty acids (EpFA) is a compound in Table 4 selected from the group consisting of:
 a) compound 1860 (1-Adamantan-1-yl-3-[1-(4-methanesulfonyl-phenyl)-5-phenyl-1H-pyrazol-3-ylmethyl]-urea), 
 b) compound 2321 (1-Cycloheptyl-3-[1-(4-methanesulfonyl-phenyl)-5-phenyl-1H-pyrazol-3-ylmethyl]-urea), 
 c) compound 2322 (1-[1-(4-Methanesulfonyl-phenyl)-5-phenyl-1H-pyrazol-3-ylmethyl]-3-phenyl-urea), 
 d) compound 2323 (1-[1-(4-Methanesulfonyl-phenyl)-5-phenyl-1H-pyrazol-3-ylmethyl]-3-(4-trifluoromethoxy-phenyl)-urea), 
 e) compound 2324 (1-[1-(4-Methanesulfonyl-phenyl)-5-phenyl-1H-pyrazol-3-ylmethyl]-3-(4-trifluoromethyl-phenyl)-urea), 
 f) compound 1861 (1-[1-(4-Methanesulfonyl-phenyl)-5-phenyl-1H-pyrazol-3-ylmethyl]-3-(3-trifluoromethyl-phenyl)-urea), 
 g) compound 2107 (4-{5-Phenyl-3-[3-(3-trifluoromethyl-phenyl)-ureidomethyl]-pyrazol-1-yl}-benzenesulfonamide), 
 h) compound 2106 (1-[5-tert-Butyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazol-3-ylmethyl]-3-(3-trifluoromethyl-phenyl)-urea), 
 i) compound 2121 (4-{5-Phenyl-3-[3-(3-trifluoromethyl-phenyl)-ureido]-pyrazol-1-yl}-benzenesulfonamide), 
 j) compound 2313 (4-(5-Phenyl-3-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-ethyl)-pyrazol-1-yl}-benzenesulfonamide), 
 compound 1862 (1-{3-[1-(4-Methanesulfonyl-phenyl)-5-phenyl-1H-pyrazol-3-yl]-propyl}-3-(3-trifluoromethyl-phenyl)-urea), 
 k) compound 2246 (4-(5-Phenyl-3-{3-[3-(3-trifluoromethyl-phenyl)-ureido]-propyl}-pyrazol-1-yl)-benzenesulfonamide), 
 l) compound 2152 (4-(5-p-Tolyl-3-{3-[3-(3-trifluoromethyl-phenyl)-ureido]-propyl}-pyrazol-1-yl)-benzenesulfonamide), 
 m) compound 2325 (4-(3-{3-[3-(2,6-Diisopropyl-phenyl)-ureido]-propyl}-5-phenyl-pyrazol-1-yl)-benzenesulfonamide), 
 n) compound 2245 (4-{5-Phenyl-3-[3-(3-phenyl-ureido)-propyl]-pyrazol-1-yl}-benzenesulfonamide), 
 o) compound 2326 (4-{3-[3-(3-Adamantan-1-yl-ureido)-propyl]-5-phenyl-pyrazol-1-yl}-benzenesulfonamide), 
 p) compound 2247 (4-{3-[3-(3-Cycloheptyl-ureido)-propyl]-5-phenyl-pyrazol-1-yl}-benzenesulfonamide), 
 q) compound 2327 (4-(3-{3-[3-(4-Chloro-phenyl)-ureido]-propyl}-5-phenyl-pyrazol-1-yl)-benzenesulfonamide), 
 r) compound 2328 (4-(5-Phenyl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-propyl}-pyrazol-1-yl)-benzenesulfonamide); and 
 s) compound 2329 (4-(5-Phenyl-3-{3-[3-(4-trifluoromethoxy-phenyl)-ureido]-propyl}-pyrazol-1-yl)-benzenesulfonamide). 
 
     
     
       15. The method  claim 1 , wherein the stem cells are human induced pluripotent stem cells (hiPSCs)—derived cardiomyocytes (hiPSC-CMs). 
     
     
       16. The method of  claim 1 , wherein the tissue is cardiac tissue.